Compositions for treatment of cancer
The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain.
1. A pharmaceutical composition comprising an antitumor effective amount of a population of human T cells, wherein the cells of the population include cells that comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising the amino acid sequence of SEQ ID NO: 20, a CD8α hinge domain, a CD8α transmembrane domain, a 4-1BB costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO:24, wherein the T cells are T cells of a human having a hematological cancer.
2. The composition of claim 1 , wherein the anti-tumor effective amount of T cells is 10 4 to 10 9 cells per kg body weight of a human in need of such cells.
3. The composition of claim 1 , wherein the anti-tumor effective amount of T cells is 10 5 to 10 6 cells per kg body weight of a human in need of such cells.
4. The composition of claim 1 , wherein the CD8α transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22.
5. The composition of claim 1 , wherein the CD8α hinge domain comprises the amino acid sequence of SEQ ID NO: 21.
6. The composition of claim 1 , wherein the 4-1BB costimulatory signaling region comprises the amino acid sequence of SEQ ID NO: 23.
7. The composition of claim 1 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 18.
8. The composition of claim 4 , wherein the CD8α transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 16.
9. The composition of claim 5 , wherein the CD8α hinge domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 15.
10. The composition of claim 6 , wherein the 4-1BB costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 17.
11. The composition of claim 4 , wherein the 4-1BB costimulatory signaling region comprises the amino acid sequence of SEQ ID NO: 23.
12. The composition of claim 11 , wherein the 4-1BB costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 17.
13. The composition of claim 5 , wherein the 4-1BB costimulatory signaling region comprises the amino acid sequence of SEQ ID NO: 23.
14. The composition of claim 13 , wherein the 4-1BB costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 17.
15. The composition of claim 4 , wherein the CD8α hinge domain comprises the amino acid sequence of SEQ ID NO: 21.
16. The composition of claim 15 , wherein the CD8α hinge domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 15.
17. The composition of claim 1 , wherein the hematological cancer is leukemia or lymphoma.
18. The composition of claim 17 , wherein the leukemia is chronic lymphocytic leukemia (CLL) or acute lymphocytic leukemia (ALL).
19. The composition of claim 17 , wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.
20. The composition of claim 1 , wherein the hematological cancer is multiple myeloma.
21. A pharmaceutical composition comprising an antitumor effective amount of a population of human T cells, wherein the cells of the population include cells that comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising the amino acid sequence of SEQ ID NO: 20, a CD8α hinge domain comprising the amino acid sequence of SEQ ID NO: 21, a CD8α transmembrane domain comprising the amino acid sequence of SEQ ID NO: 22, a 4-1BB costimulatory signaling region comprising the amino acid sequence of SEQ ID NO: 23, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO:24, wherein the T cells are T cells of a human having a hematological cancer.
22. The composition of claim 21 , wherein the CD19 antigen binding domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 14, the CD8α hinge domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 15, the CD8α transmembrane domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 16, the 4-1BB costimulatory signaling region of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO: 17, and the CD3 zeta signaling domain of the CAR is encoded by a nucleic acid sequence of SEQ ID NO: 18.
23. The composition of claim 21 , wherein the anti-tumor effective amount of T cells is 10 4 to 10 9 cells per kg body weight of a human in need of such cells.
24. The composition of claim 21 , wherein the anti-tumor effective amount of T cells is 10 5 to 10 6 cells per kg body weight of a human in need of such cells.
25. The composition of claim 21 , wherein the CAR comprises the amino acid sequence of SEQ ID NO: 12.
26. The composition of claim 25 , wherein the nucleic acid sequence encoding the CAR comprises the nucleic acid sequence of SEQ ID NO: 8.
27. The composition of claim 21 , wherein the hematological cancer is leukemia or lymphoma.
28. The composition of claim 27 , wherein the leukemia is chronic lymphocytic leukemia (CLL) or acute lymphocytic leukemia (ALL).
29. The composition of claim 27 , wherein the lymphoma is mantle cell lymphoma, non-Hodgkin's lymphoma or Hodgkin's lymphoma.
30. The composition of claim 21 , wherein the hematological cancer is multiple myeloma.